Crotamine Pharmacology Revisited: Novel Insights Based on the Inhibition of K-V Channels

Crotamine, a 5-kDa peptide, possesses a unique biological versatility. Not only has its cell-penetrating activity become of clinical interest but, moreover, its potential selective antitumor activity is of great pharmacological importance. In the past, several studies have attempted to elucidate the exact molecular target responsible for the crotamine-induced skeletal muscle spasm. The aim of this study was to investigate whether crotamine affects voltage-gated potassium (K-V) channels in an effort to explain its in vivo effects. Crotamine was studied on ion channel function using the two-electrode voltage clamp technique on 16 cloned ion channels (12 K-V channels and 4 Na-V channels), expressed in Xenopus laevis oocytes. Crotamine selectively inhibits K-V 1.1, K-V 1.2, and K-V 1.3 channels with an IC50 of similar to 300 nM, and the key amino acids responsible for this molecular interaction are suggested. Our results demonstrate for the first time that the symptoms, which are observed in the typical crotamine syndrome, may result from the inhibition of K-V channels. The ability of crotamine to inhibit the potassium current through K-V channels unravels it as the first snake peptide with the unique multifunctionality of cell-penetrating and antitumoral activity combined with K-V channel-inhibiting properties. This new property of crotamine might explain some experimental observations and opens new perspectives on pharmacological uses.Fundacao de Amparo a Pesquisa do Estado de Sao PauloFundacao de Amparo a Pesquisa do Estado de Sao Paulo [2009/07128-7]Programa de Apoio a PosgraduacaoCoordenacao de Aperfeicoamento de Pessoal de Nivel Superior (Brazilian Government)Programa de Apoio a Pos-graduacao-Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (Brazilian Government)Conselho Nacional de Desenvolvimento Cientifico e TecnologicoConselho Nacional de Desenvolvimento Cientifico e Tecnologico [490194/2007-9]Fonds Wetenschappelijk Onderzoek Vlaanderen [G.0257.08, G.0330.06]Fonds Wetenschappelijk Onderzoek VlaanderenOnderzoeks Traject K.U. LeuvenOnderzoeks Traject K.U. Leuven [05-64]Universitaire Attractie Pool 6/31 (Interuniversity Attraction Poles)Universitaire Attractie Pool 6/31 (Interuniversity Attraction Poles